Indenopyran-and indenothiopyran alkylamines

ABSTRACT

INDENOPYRAN- AND INDENOTHIOPYRANALKYLAMINE DERIVATIVES CHARACTERIZED BY HAVING AN AMINO (LOWER) ALKYL RADICAL ATTACHED TO HE 1 POSITION OF A INDENO(2,1-C)PYRAN OR INDENO(2,1-C)THIOPYRAN NUCLEUS ARE DISCLOSED. THE AMINO PORTION OF THE AMINO(LOWER) ALKYL RADICAL MAY BE FURTHER SUBSTITUTED WITH ONE OR TWO LOWER ALKYL GROUPS OR INCORPORATED INTO A HETEROCYCLIC AMINE RADICAL. THE DERIVATIVES ARE FURTHER SUBSTITUTED AT POSITION 1 AND MAYBE OPTIONALLY SUBSTITUTED AT POSITIONS 3, 4, 5, 6, 7, 8, AND 9. THE INDENOPYRAN- AND INDENOTHIOPYRANALKYLAMINE DERIVATIVES OF THIS INVENTION ARE USEFUL ANTIDEPRESSANT AGENTS. METHODS FOR THEIR PREPARATION AND USE ARE DISCLOSED.

United States Patent ()1 ice 3,778,449 Patented Dec. 11, 1973 Int. Cl.A61k 27/00; C07d 65/04, 7/18 US. Cl. 260-327 TH 9 Claims ABSTRACT OF THEDISCLOSURE Indenopyranand indenothiopyranalkylamine derivativescharacterized by having an amino(lower) alkyl radical attached to the 1position of a indeno[2,1-c]pyran or indeno[2,1-c]thiopyran nucleus aredisclosed. The amino portion of the amino(lower) alkyl radical may befurther substituted with one or two lower alkyl groups or incorporatedinto a heterocyclic amine radical. The derivatives are furthersubstituted at position 1 and may be optionally substituted at positions3, 4, 5, 6, 7, 8, and 9. The indenopyranand indenothiopyranalkylaminederivatives of this invention are useful antidepressant agents. Methodsfor their preparation and use are disclosed.

BACKGROUND OF THE INVENTION (1) Field of invention Prior interest in thefield of indenopyrans and indenothiopyrans has been so limited that itmay be considered practically non-existent. Apparently, the closestprior art to the compounds of the present invention would be a fewunrelated reports dealing with chemical aspects of certain compoundswith indenopyran ring systems. For example, in a report by N. Campbell,et al., J. Chem. Soc., 993 (1963), the authors postulate that certainneutral indeno[2,1-c] or indeno[1,2-c]pyran derivatives may be producedby the reaction of 2-benzylideneindan-1-one and diphenylketene.

SUMMARY OF THE INVENTION The indenopyranand indenothiopyranalkylaminederivatives of this invention are characterized by having anamino(lower)alkyl radical attached to a indeno[2,1-c] pyran orindeno[2,1-c]thiopyran nucleus. The preferred derivatives of thisinvention are repersented by Formula I, I

in which R is lower alkyl; R R R and R are the same or differentselected from the group consisting of bydrogen and lower alkyl; R ishydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy or halo;R" is hydrogen or lower alkyl; X is oxy or thio; and Y is anamino(loweralky1 radical of formula AlkNR R wherein Alk is an alkyleneselected from the group consisting of CR R CR R CR RCR10R11CR12R13CR14R15 and CR R CR R CR R CR R wherein R R R R R R R andR are hydrogen or lower alkyl and R and R are either the same ordifferent selected from the group consisting of hydrogen and loweralkyl, or R and R together with the nitrogen atom to which they arejoined form a heterocyclic amine radical selected from the groupconsisting of l-pyrrolidinyl, piperidino, morpholino, piperazino,4-(lower alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as usedherein contemplates straight chain alkyl radicals containing from one tosix carbon atoms and branched chain alkyl radicals containing three tofour carbon atoms and includes methyl, ethyl propyl, isopropyl, butyl,isobutyl, pentyl and the like.

The term lower alkoxy as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy and the like.

The term lower alkanoyloxy as used herein contemplates both straight andbranched chain alkanoyloxy radicals containing from two to six carbonatoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The term halo as used herein contemplates halogens and includesfluorine, chlorine, bromine and iodine.

The indenopyranand indenothiopyranalkylamines of Formula I are capableof forming acid addition salts with pharmaceutically acceptable acids.Such acid addition salts are included within the scope of thisinvention.

The acid addition salts are prepared by reacting the base form of theappropriate indenopyranand indenothiopyranalkylamines of Formula I withsubstantially one or two equivalents, depending on the number of basicnitrogens in the compound, or preferably with an excess of theappropriate acid in an organic solvent, for example, ether or anethanol-ether mixture. These salts, when administered to mammals,possess the same pharmacologic activities as the corresponding bases.

For many purposes it is preferable to administer the salts rather thanthe base compounds. Among the acid addition salts suitable for thispurpose are salts such as the sulfate, phosphate, lactate, tartrate,maleate, citrate, hydrobromide and hydrochloride. Both the basecompounds and the salts have the distinct advantage of possessing arelatively low order of toxicity.

Also included in this invention are the stereochemical isomers of thecompounds of Formula I which result from asymmetric centers, containedtherein. These isomeric forms may be prepared by chemical methods andare purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereo-isomeric salts formed thereof, forinstance, with dor l-tartaric acid or D-(+)-a-bromocamphor sulfonicacid, are also included.

ANTIDEPRESSANTQ AcrrvrrY The useful antidepressant activity of theindenopyranand indenothiopyranalkylamines of Formula I and their acidaddition salts with pharmaceutically acceptable acids may bedemonstrated in standard pharmacologic tests, such as, for example, thetests described by F. Hafliger and V. Bruckhart in PsychopharmacologicalAgents, M.

3 Gordon, ed., Academic Press, New York and London, 1964, pp. 75-83.

More specifically, as noted in the latter reference the antidepressantproperties of a compound may be demonstrated by its capacity toantagonize the depressant effects of reserpine. Furthermore, it is welldocumented that reserpine in animals produces a model depression whichcan be used for detecting antidepressant properties. Accordingly, thecompounds of the present invention antagonize reserpine efl'ects in miceat doses ranging from about 1 to 100 mg./kg. Several of the preferredcompounds, for instance,

N,N,l-trimethyl-1,3,4,9-tetrahydroindeno[2,1-c]

pyran-l-ethylamine hydrochloride (Example 284);

N,N, l-trimethy1-1,3 ,4,9-tetrahydroindeno [2, l-c] pyranl-propylaminehydrochloride (Example 287); and

N,N,l-trimethyl-1,3,4,9-tetrahydroindeno[2,1-c]thiopyran-l-ethylaminehydrochloride (Example 373),

antagonize the effects of reserpine in mice at dose ranges from about 1to mg./kg.

The compounds of the present invention are also particularly noteworthyin that they block substantially the uptake of serotonin. This property,which is readily demonstrated in the test of D. F. Bogdanski et al., J.Pharmac. Exp. Ther., 122, 182 (1958), is a desirable feature for atherapeutic agent used to alleviate the symptoms of depressionespecially when it is desired primarily to elevate the mood of thepatient.

When the indenopyranand indenothiopyranalkylamines of this invention areused to relieve the symptoms of depression in warm-blooded mammals, e.g.rats and mice, they may be used alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard biological practice. For example,they may be administered orally in solid form containing such excepientsas starch, milk sugar, certain types of clay and so forth. They may alsobe administered orally in the form of solutions or they may be injectedparenterally. For parenteral administration they may be used in the formof a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstance is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side eifects and preferably at alevel that is in a range of from about 0.1 mg. to about 50 mg. per kiloper day, although as aforementioned variations will occur. However, adosage level that is in the range of from about 0.5 mg. to about 25 mg.per kilo per day is most desirably employed in order to achieveeffective results.

PROCESSES For the preparation of the indenopyranandindenothiopyranalkylamine derivatives of this invention we prefer to useas starting materials the compounds of general Formula H,

Ra a M41 R ,L. 1.. \r/

E (II) 4 in which R R R R R and R are as defined in the first instanceand X is hydroxy or mercapto.

The starting material of Formula 'II, indene-3-ethanol (II; X =OH and RR R R R and R' -=H), is well known and its synthesis by a variety ofmethods has been reported; for example, see G. R. Clemo, et al., J. ChemSoc., 863 (1951), and F. H. Howell and D. A. H. Taylor, J. Chem Soc.,3011 (1957). For the preparation of this starting material as well asthe other requisite starting materials of Formula II in which X ishydroxy the following two general processes are convenient.

The first process may be illustrated as follows:

CHIUCHzCO OH (III) C R 000 R With reference to this first process thecyclization of the appropriate phenylpropionic acid derivative, seeChemistry of Carbon Compounds, vol. III A, E. H. Rodd, ed., ElsevierPublishing Co., Amsterdam, 1954, pp. 593-598, is accomplished bytreatment with an acid, for example, anhydrous hydrofluoric acid,according to the conditions described by J. A. Elvidge and R. G. Foster,J. Chem. Soc., 590 (1963), to give the corresponding indanone of FormulaIV. The latter compound is treated with the appropriate Reformatskiireagent of formula in which Y is bromine or chlorine, R is lower alkyland R and R are as defined hereinbefore, followed by dehydration of theproduct, see Organic Reactions, vol. 1, R. Adams, et al., eds., JohnWiley and Sons, Inc., New York, 1942, p. 1 and K. Brewster, et al., J.Chem. Soc., 941 (1972), to give the endo ester V or a mixture thereofwith the exo ester VI in the case Where R of the Reformatskii reagent ishydrogen. The ester V or the mixture of the latter esters are thenreduced by lithium aluminum hydride and the desired compound of FormulaII (X =OH and R and R =H) separated from the reaction product byconventional means such as chromatography or recrystallization.

The second process may be illustrated as follows:

(VII) (VIII) With reference to this second process the appropriateindene derivative of Formula VII, see Chemistry of the Carbon Compounds,vol. III B, cited above, 1956, pp. 1256-1261, A. Panetta and S. C.Bunce, J. Org. Chem., 4859 (1961) and M. L. Tamayo and N. D. Robles,Anales Real Soc. Espan. Fis. Y. Quim., 52B, 117 (1956),

[Chem.'Abst., 50, 14676 (1956)], is converted to its correspondinglithium derivative by treatment 'with butyl lithium in tetrahydrofuran.The corresponding lithium derivative is thentreated with ethylene oxideor a lower alkyl substituted ethylene oxide to afford the desiredstarting material of Formula I, in which X is hydroxy. The desiredstarting materials may also be obtained by treating the appropriateindene derivative of Formula VII with the appropriate ethylene oxidederivative according'to the procedure of M. Julia, et al., Bull. Soc.Chim. Fr., 2291 (1966), for reacting ethylene oxide with indole.

The lower alkyl substituted ethylene oxides are prepared by knownmethods; for example, see V. Franzen and H. E. Driesen, Chem. Ber., 96,1881 (1963).

The starting materials of Formula II in which X is mercapto and R R R RR and R are as defined in the first instance may be obtained by thefollowing process: The appropriate compound of Formula II (X =OH),described above, is treated with phosphorus tribromide in an inertsolvent, for example, ether or carbon tetrachloride, to afford thecorresponding 3-(2- bromoethyl)indene derivative. In the case 'where Xis hydroxy and R R R R R and R are hydrogen, the corresponding3-(2-bromoethyl)indene derivative obtained is 3-(2-bromoethyl)indeneitself, also described by R. Clemo, et al., J. Chem. Soc., 863 (1951).The 3-(2- bromoethyl)indene derivative so obtained is then converted tothe desired starting material of Formula II (X =SH) by a proceduresimilar to that described by N. N. Suvorov and V. N. Buyanov,Khim.-Farm. Zh., 1, (1967), [Chem Abstr. 67, 7347421 (1967)], forconverting 3-(2-bromoethyl)-indole to indo1e-3-ethanethiol.

Accordingly, the appropriate 3-(2-bromoethyl)-indene derivative istreated with sodium or potassium thiosulfate to afford the correspondingsodium or potassium fl-(3- indeny1)-ethyl thiosulfate derivative,respectively, which on treatment with strong alkali for example, sodiumor potassium hydroxide, is transformed into the corresponding bis [w (3indenyl)-ethyl] disulfide derivative. Reduction of the latter compoundwith lithium aluminum hydride gives the desired compound of Formula II.

It should be noted that the preceeding process may not be entirelypractical for the preparation of the compounds of Formula II in which Xis mercapto and R is bydroxy or lower alkanoyloxy. For this reason, thepreferred starting materials of Formula II for the ultimate preparationof the compounds of Formula I in which R is hydroxy or lower alkanoyloxyand X is thio are the corresponding compounds of Formula II in which Ris benzyloxy, i.e., a hydroxyl with a protecting benzyl group or othersuitable protecting group, see I. F. Mc- Omie, Advances in OrganicChemistry, vol. 3, R. A. Raphael, et al., ed., Interscience Publishers,New York, 1963, pp. 191-294. When the latter compounds are used asstarting materials in this manner, they are first subjected to theprocess (II+IX X), described below. Subsequently, the benzyloxy group isremoved by hydrogenation, inthe presence of a catalyst, for example,palladium on carbon, just prior to afiording the desired correspondingcompound of Formula I in which R is hydroxy. The latter may be convertedif desired to the corresponding. compound of Formula I in which R islower alkanoyloxy by conventional means, for example, by treatment withthe appropriate lower alkanoic anhydride preferably in the presence ofpyridine.

Likewise, it should be noted that similar use of the starting materialsof Formula II in which X is hydroxy and R is benzyloxy to obtain thecorresponding compound of Formula I in which R is hydroxy or loweralkanoyloxy is also preferred.

The above described starting materials of Formula II in which R R R R RR" .and X are as defined in the first instance are now subjected to akey reaction comprising the treatment of said starting materials withsubstantially an equivalent amount of a compound of formula in which Ris as defined in the first instance and Y is selected from the groupconsisting of:

(a) COOR and Alk COOR in which R is hydrogen or lower alkyl and Alk isan alkylene selected from the group consisting of CR R CR R CR R and CRR CR R CR R wherein R R R R R and R are hydrogen or lower alkyl,

(b) CONR R and Alk CONR R in which Alk R and R are as definedhereinbefore,

(c) CH 0COR and Alk --CH 0COR in which R is hydrogen or lower alkyl andAlk is as defined hereinbefore,

(d) Alk -L in which Alk is an alkylene selected from the groupconsisting of CR R CHR m n m m n and CR R CR R CR R CHR wherein R R R RR R and R are as defined hereinbefore and L is halo,

(e) Alk NR COR in which and R are as defined herein and R is hydrogen orlower alkyl containing from one to five carbon atoms,

(f) AlkNO in which Alk is as defined hereinbefore, and

(g) AlkNR R in which Alk, R and R are as defined hereinbefore, in thepresence of an acid catalyst to yield the compounds of Formula X inwhich R R R R R R R", X and Y are as defined hereinbefore aminecompounds of Formula I as in the case when Y of is AlkNR R as definedhereinbefore.

When practising the condensation (H+IX X) a solvent is generally used asa reaction medium. Any solvent inert to the reaction conditions may beused. Suitable solvents include benzene, toluene, diethyl ether, dioxan,tetrahydrofuran, methylene dichloride, carbon tetrachloride and thelike. Benzene and tetrahydrofuran are especially convenient andpractical for this use. However, note that the solvent may be omittedwithout detrimental effects on the reaction it the reactants are heatedto a melt with stirring.

A variety of suitable acid catalysts may be used for this condensation,for example, the type of catalyst used in a Friedel-Crafts reaction,i.e., p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide,boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid,trifluoroacetic acid, sulfuric acid, and polyphosphoric acid and thelike. Boron trifluoride, p-toluenesulfonic acid, aluminum chloride, andtrifluoroacetic acid are included among the preferred acid catalysts.The amount of acid catalyst used is not especially critical and mayrange from 0.01 molar equivalents to molar equivalents with respect tothe starting material of Formula 'II. A range of from 0.1 to 10 molarequivalents is generally preferred; however, note that the amount ofacid catalyst 7 should be in excess of one molar equivalent with respectto the compound of formula n ll-Y when Y is AlkNR R The time of thereaction may range from 10 minutes to 60 hours, with the preferred rangebeing from one-half to 24 hours. The temperature of the reaction mayrange from 20 C. to 160 C.

A more detailed description of the preparation of the above compounds ofFormula X and a description of their subsequent conversion toindenopyranand indenothiopyranalkylamine derivatives of Formula I aredisclosed below. For convenience these descriptions are catagorized intosections according to the group selected for Y for the intermediate.

(a) Preparation and conversion of intermediates of Formula X (Y =COORand Alk COOR Intermediates of Formula X (Y =COOR and A1k --COOR whereinR is hydrogen or lower alkyl and Alk is as defined in the firstinstance) are readily obtained by the condensation (II+IX- X) by usingketoacids or ketoesters of formula in which R is as defined in the firstinstance and Y is COOR or Alk -COOR as defined above together with thestarting material of Formula II.

Generally comparable yields of product are obtained in this process wheneither the ketoacid or the corresponding ketoester is used. However, inthe case where it is desired to prepare an acid compound of Formula X inwhich Y is Alk COOR wherein Alk is CR R and R is hydrogen (i.e., an acidintermediate of Formula X), it is preferable to first condense theappropriate fi-ketoester of Formula IX rather than the correspondingli-ketoacid and then hydrolyze the resulting ester product to give thedesired acid compound.

Moreover, in the general practice of this invention it is often moreconvenient to prepare the acid compounds of Formula X by using theketoester instead of the ketoacid in this process and hydrolyze theresulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

The hydrolysis of compounds of Formula X in which Y is COOR or Alk COORwherein Alk is as defined in the first instance and R is lower alkyl,i.e. ester intermediates of 'Formula X, to their corresponding acids ofFormula X, is readily effected by treatment with a suitable alkali, forexample, potassium hydroxide or sodium carbonate, in aqueous methanol oraqueous ethanol or by treatment with lithium iodide in a suitableorganic solvent, for example, collidine, see L. F. Fieser and M. Fieser,Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York,1967, pp. 615-617.

The 11-, 6-, 'yand fi-ketoacids and -ketoesters of Formula IX are eitherknown, for example, ethyl pyruvate, levulinic acid, ethyla,a-dimethylacetoacetate, and 5,;8-dimethyllevulic acid, or they may beprepared by known methods described in general organic chemistrytextbooks. For example, a comprehensive review of the properties andpreparation of such or, 13-, 'y and 6-ketoacids and ketoesters may befound in Rodds Chemistry of the Carbon Compounds, S. Coffey, ed., vol.1d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, 226-274.

Thereafter these intermediate acids and esters of Formula X areconverted by amidation followed by reduction to compounds of Formula Iin which R R R R and R R, R and X are as defined in the first instanceand Y is -Alk--NR R in which Alk is CH;

8 or Alk --CH wherein Alk is as defined in the first instance.

More specifically, in the case where the acid intermediate of Formula Xis employed, said acid is subjected to amidation by treatment with alower alkyl chloroformate, preferably ethyl chloroformate, in thepresence of triethylamine, affording the corresponding mixed anhydride,which is converted by treatment with the appropriate amine of formulaHNR R in which R and R are as defined in the first instance, forexample, ammonia, methylamine or dimethylamine, to yield thecorresponding amide of Formula X in which Y is CONR R or Alk CONR 'R inwhich Alk R and R are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the esterintermediates of Formula IX with the appropriate amine according toknown amidationi methods, for example, see A. L. F. Beckwith in TheChemistry of Amides, I. Zalicky, ed., Interscience Publishers, New York,1970, pp. 96-105.

Thereafter, the amides so obtained are reduced with a suitable complexmetal hydride to yield the desired indenopyranandindenothiopyranalkylamines. Examples of suitable complex metal hydridesare lithium aluminum hydride, lithium aluminum hydride-aluminumchloride, aluminum hydride-aluminum chloride, diborane and sodiumborohydride-aluminum chloride. Lithium aluminum hydride is preferred.

A modification relating to the preceding general reduction of the aboveamides of Formula X in which Y is CONRR or Alk -CONR R wherein Alk R andR is as defined in the first instance is applicable to the reduction ofthe tertiary, secondary and primary amides, described herein, and is apreferred modification for the reduction of the latter two. Inpractising this modification, the aforementioned amide of Formula X istreated with triethyloxonium fluoroborate or dimethyl sulfate, see H.Bredereck, et al., Chem. Ber., 98, 2754 (1965), in an inert solvent, forexample, methylene dichloride, whereby the corresponding iminoetherfluoroborate or methyl sulfate salt is obtained, respectively.Subsequent reduction of the salt thus obtained with a complex metalhydride, similar to the reduction described previously for the amides,yields the corresponding compounds of Formula I. Alternatively, theabove fiuoroborate or methyl sulfate salt derived from a secondary orprimary amide may be decomposed by base treatment, for example, with 10%sodium hydride or triethylamine, to give the corresponding iminoetherwhich is then reduced in a like manner to the desired compound ofFormulaI.

When applying the aforementioned steps in the preparation of compoundsof Formula I in which R is hydroxy or lower alkanoyloxy, it ispreferable to use corresponding intermediates in which R is benzyloxyfollowed by the appropriate transformations as noted previously to yieldthe desired compounds of Formula I.

(b) Preparation and conversion of intermediates of Formula X (Y =CONR Rand Alk CONR R The intermediates of Formula X in which Y is CONR R andAlk -CONR 'R wherein R, R and Alk are as defined in the first instance,described in the previous section, are also obtained directly byutilizing the appropriate starting materials of Formula II and a-, 8-,or fi-ketoamides of formula in which R is as defined above and Y is CONRR or Alk --CONR R in which Alk R and R are as defined above. Theketoamides required for this condensation are either known, for example,pyruvamide or a,a-dimethylacetoacetamide, or they may be prepared byknown methods, for instance, see Rodds Chemistry of the CarbonCompounds, cited above, vol. 1d, pp. 226-274.

Thereafter these amides are converted by the reduction process,described above, to the compounds of Formula I in which R R R R R R Rand X are as defined in the first instance and Y is -Alk--NRR in whichAlk is CH or Alk -CH wherein Alk is as defined in the first instance,and R and R are as defined in the first instance.

(c) Preparation and conversion of intermediates of Formula (Y =OH OCORand Alk -CH OCOR Intermediates of Formula X in which Y is CH OCOR andAlk ---CH OCOR wheerin Alk and R are as defined in the first instance,are obtained when a starting material of Formula II is condensed with aketoalcohol lower alkanoic acid ester of formula R COCH OCO'R or R'CO-Alk CH OCOR in which R Alk and R are as defined in the firstinstance in the presence of a suitable acid catalyst according to theconditions described above for the condensation (II'+IX- X). Theketoalcohol lower alkyl esters are either known, for example, acetonylacetate or 5-acetoxypentan-2-one, or may be prepared by known methods,for instance, see Rodds Chemistry of the Carbon Compounds? cited above,vol. Id, pp. 49-54. These intermediates of Formula X are utilized forthe preparation of compounds of Formula I of this invention in thefollowing manner: The intermediate is hydrolyzed with an aqueousalcoholic solution of a suitable alkali, for example, sodium hydroxidein aqueous methanol to afford the corresponding primary alcohol. Itshould be noted also that the latter primary alcohol is obtaineddirectly by the reduction of the appropriate intermediate acids orintermediate esters-of Formula X, described herein in section (a), usinga suitable complex metal hydride as described therein. The primaryalcohol is then oxidized to the corresponding aldehyde. Although avariety of methods are known for the oxidation of a primary alcohol toits corresponding aldehyde, see for example, Rodds Chemistry of theCarbon Compounds, cited above, vol. 10, pp. 4- 10, we have found themethod of K. E. Pfitzner and J. G. Molfat, J. Am. Chem. Soc., 87, 5670(1965), using N,N- dicyclohexylcarbodiimide and dimethyl sulfoxide inthe presence of a suitable acid, for example, trifluoroacetic acid, tobe both efficacious and convenient. Thereafter the aldehyde is reactedwith an amine of the formula HNR R in whcih R and R are as defined inthe first instance according to the method of K. N. Campbell, et al., J.Amer. Chem. Soc., 70 3868 (1948), in the case when the amine used isammonia or a primary amine, or according to the method of N. J. Leonardand J. V. Paukstelis, J. Org. Chem, 28, 1937 (1963), when the amine is asecondary amine, to give the corresponding Schiff base or immonium salt,respectively. The product so obtained is reduced with sodiumborohydride, see E. Schenker, Angew. Chem., 73, 81 (1961), to yieldcompounds of Formula I in which R R R R R R R and X are as defined inthe first instance and Y is ---Alk----NR R in which Alk is CH or Alk CHand R and R are as defined in the first instance.

Alternatively, the latter compounds of Formula I are obtained byconverting the above corresponding alcohol to a reactive intermediatesuch as the corresponding halide, fesylate or tosylate, which is thenreacted with two or more molar equivalents of an amine of formula HNR Rin which R and R are as defined in the first instance. Preferably thisreaction is perofrmed in a suitable inert solvent, for example,tetrahydrofuran, at the boiling point of the reaction mixture for aperiod of eight to 24 hours. In connection with alkylations of amines offormula HNR R in which R is hydrogen and R is lower alkyl as disclosedherein, it is generally preferable to perform the alkylation with thecorresponding N-benzyl derivative of said amine, i.e., an amine offorfula HNR R in which R is benzyl and R is lower alkyl. Thereafter,when all'appropriate transformation have been performed, the N-benzylgroup may 10 be removed by hydrogenolysis with a catalyst, preferably10% palladium on carbon, to give the desired compounds of Formula I.

. Alternatively, the above aldehyde is oxidized with a suitableoxidizing agent to yield the corresponding acid intermediates of FormulaX described in section (a). Although a variety of suitable oxidizingagents may be used for this purpose, for example, silver oxide, alkalinepermanganate, hydrogen peroxide, we prefer to use silver oxide accordingto the method of M. Delepine and P. Bonnet, Compt. rend., 149, 39(1909).

Again alternatively, the above aldehyde is converted to its oxime whichon reduction with a complex metal hydride yields the correspondingprimary amine of Formula I in which R, R R R R R", R and X are asdefined in the first instance and Y is AlkNR R in which Alk is CH or AlkCH wherein Alk is as defined in the first instance and R and R arehydrogen.

If desired the latter compounds of Formula I may be further N-alkylatedon the nitrogen of the primary amine with the appropriate lower alkylhalide to the corresponding compounds of Formula I in which Y is-Alk--NR R wherein Alk is CH or Alk -CH wherein Alk is as defined in thefirst instance and R is hydrogen or lower alkyl and R is lower alkyl(i.e. secondary or tertiary amines with respect to Y). In this casedepending on the particular derivatives desired the N-alkylation may beeffected with one or two moles of the alkyl halide to give respectivelythe secondary (R =H and R =lower alkyl) or tertiary amine (R =R =loweralkyl). On the other hand the N- alkylation may be effected in two stepsintroducing a different alkyl group each time to afford thecorresponding tertiary amine in which R and R are different loweralkyls.

When it is desired to prepare the above tertiary amine compounds inwhich R or R are either or both methyl, an alternative alkylation methodcomprises reacting the apppropriate corresponding primary or secondaryamine with an aqueous mixture of a substantial excess of formaldehydeand formic acid according to the conditions of the Eschweiler-Clarkreaction, see M. L. Moore, Organic 'Reactions, 5, 301 (1949), wherebyN-methylation is effected.

Another N-alkylation method which may be applied to the above primaryand secondary amines involves acylation with a lower alkanoic anhydrideor acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines may be used to prepare compoundsof Formula 1 in which Y is wherein Alk is CH or Alk -CH and R and Rtogether with the nitrogen atom to which they are joined from aheterocyclic amine radical as defined in the first instance. When usedin the manner the primary amines are subjected to known N-alkylationmethods, for example, see method I described by R. B. Moffet, J. Org.Chem, 14, 862 (1949), with the appropriate m-w-dibromides, for example,tetramethylene dibromide, pentamethylene dibromide, bis(2-chloroethyl)ether, bis(2-chloroethyl)benzylamine followed byhydrogenation in the presence of 10% palladium on carbon to remove theprotecting benzyl group, a bis(2- chloroethyl)-lower alkylamine or abis(2-chloroethyl-N- [hydroxy(lower)-alkyl]amine, to give thecorresponding desired compound of Formula I wherein Y is an amino(lower)alkyl in which the amino portion thereof is l-pyrrolidinyl,piperidino, morpholino, piperazino, 4-(loweralkyl)-1-piperazinyl or4-[hydroxy(lower)alkyl]-1-piperazinyl, respectively. I

(d) Preparation and conversion of intermediates of Formula X (Y =Alk L)Intermediates of Formula X in which Y is Alk -L wherein Alk and L are asdefined in the first instance, are

I 1 obtained when a starting material of Formula II is condensed with a8-, 'yor a-haloketone of formula in which R Alk and L are as defined inthe first instance, in the presence of a suitable acid catalystaccording to the conditions described above for the condensation (II+IX-X). I

The haloketones are either known, for example, 4- chlorobutan-Z-one, orthey may be prepared by known methods, for instance, see Rodds chemistryof Carbon Compounds, cited above, vol. 1c, pp. 70-71 and Methoden derOrganischen Chemie, Houben-Weyl, E. Miiller, ed., vol. V/3, Georg ThiemeVerlag, Stuttgart, 1962, pp. 511-1076.

Thereafter these intermeditates of Formula X are treated with two molarequivalents or more of an amine of formula HNR R in which R and R are asdefined in the first instance to yield the compounds of Formula I inwhich R R R R R R, R and X are as described in the first instance and Yis AlkNR R in which Alk is Alk as defined in the first instance and Rand R are as defined in the first instance. Preferred conditions forthis reaction include the use of a suitable inert solvent, for example,tetrahydrofuran, temperatures ranging from 40- 100 C. or at the boilingpoint of the reaction mixture and a reaction time of from eight to 24hours.

(e) Preparation of conversion of intermediates of Formula X (Y =AlkNRCOR Intermediates of Formula X in which Y is AlkNR COR wherein Alk, Rand R are as defined in the first instance are readily obtained by thecondensation (II+IX- X) by using ketoamides of formula in which R Alk, Rand R are as defined in the first instance together With the appropriatestarting material of Formula II.

The ketoamides used herein are either known, for example,formamidoacetone [see A. Treibs and W. Sutter, Chem. Ber., 84, 96 (1951)and R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948)]or may be prepared by known procedures, for example, see Methoden derOrganischen Chemie, cited above, vol. XI/I, 1957, especially pp. 58-62,285-289 and 508-509, and F. F. Blicke, Organic Reactions, I, 303 (1942).

Thereafter, reduction with a complex metal hydride, described in section(a), converts the instant intermediates of Formula IX to compounds ofFormula I in which R R R R R R R", X are as defined in the firstinstance and Y is AlkNR R in which Alk and R is hydrogen or lower alkyland R is lower alkyl.

(f) Preparation and conversion of intermediates of Formula X (Y=Alk---NO Intermediates of Formula IX in which Y" is AlkNO wherein Alkis as defined in the first instance, are obtained by the condensation('II+IX- X) when the starting materials of Formula II and appropriate0c, ;8- 'yand fi-nitroketones of formula in which R and Alk are asdefined in the first instance are employed therein in the presence of asuitable acid catalyst. In this case trifluoroacetic acid is a preferredacid catalyst.

The nitroketones used herein are either known, for example,l-nitro-Z-propanone, N. Levy and C. W. Scaife,

J. Chem. Soc., 1100, (1946) and 5-nitro-2-hexanone, I. Shechter, et al.,J. Amer. Chem. Soc., 74 3664 (1952) or they may be prepared by knownmethods, for example, see Levy and Scaife, cited above, Shechter, et al.cited above, Rodds Chemistry of Carbon Compounds, cited above, vol. 1c,pp. 71-72 and Methoden der Organischen Chemie, cited above, vol X/I,1971, p. 203.

Thereafter, these intermediates of Formula X are reduced with a complexmetal hydride, preferably lithium aluminum hydride, to afford thecompounds of Formula I in which R R R R R R R' and X are as defined inthe first instance and Z is AlkNR R in which Alk is as defined in thefirst instance and R and R are hydrogen. 7

If desired the latter compounds are N-alkylated according to the methodsdescribed in section (c) to give the compounds of Formula I in which R RR R R R, R" and X are as defined in the first instance and Y is AlkNRRin which Alk is as defined in the first instance, R is hydrogen or loweralkyl and R is lower alkyl.

(g) Preparation of compounds of Formula X (Y =AlkNR R ECOHlPOlll'ld ofFormula I (Y=AlkNR R The above described starting materials of FormulaII in which R R R R R R and X are as defined in the first instance arecondensed in the presence of an acid catalyst with an aminoketone offormula in which R Alk, R and R are 'as defined in the first instance togive directly the indenopyranand indenothiopyranalkylamine derivativesof Formula I of this invention.

The requisite aminoketones for this reaction are either known, forexample, l-dimethylamino 3 butanone, 1- methylamino-B-pentanone, see F.F. Blicke, cited above, or they may be prepared by known procedures, forexample, see Methoden der Organischen Chemie, cited above, vol. XI/I,1957, pp. 58-62, 285-289 and 508-509.

In practising this present condensation it is generally advantageous toutilize substantially equimolar amounts of the starting material ofFormula II and the aminoketone in the presence of an acid catalyst. Inthis particular condensation the amount of the aforementioned acidcatalyst to employ ranges generally from about 1.01 to 100 molarequivalents with respect to the amount of aminoketone reactant, a rangeof from 1.05 to 10 molar equivalents being preferred. Optionally, onemay employ the acid addition salts of the aforementioned aminoketones,for exa-mple the hydrochloride or the sulfate salt. In this case theamount of acid catalyst may range from 0.01 to 100 molar equivalents,preferably 0.1 to 100 molar equivalents. Boron trifluoride is apreferred acid catalyst for the present condensation. The reaction maybe performed conveniently and advantageously without a solvent, althougha high boiling solvent, for example, toluene, o-xylene or isobutylether, may be used. Reaction time and temperature depends on theparticular reactants employed and may be varied. The most convenientreaction time is from one-half to 48 hours, preferably onehalf to fourhours, and reaction temperatures from 20 to 100 C., preferably 40 to C.

The following examples illustrate further this invention.

EXAMPLE 1 Indene-3-ethanethiol (II; R R R R R R =H and X =H)3-(2-bromoethyl)-indene (17 g.) is subjected to reflux for 3 hr. with asolution of 13.3 g. of sodium thiosulfate in ml. of water and 200 ml. ofethanol. The solvents are removed under reduced pressure, and theresidue dissolved in a solution of NaOH (15 g.) in 100 ml. of water.Ethanol (300 ml. is added). The solution is heated to reflux for 2 hr.,allowed to. cool, and extracted with three portionsof ether. Thecombined extracts are washed with saturated brine solution, andconcentrated. The residue is passed through a column packed with silicagel and eluted with-benzene-hexane (1:3) to yield biS-[w-(3-indenyl)ethyl]-disulfide, NMR (CDCl 6 3.02 (s., 8H), 3.33 (m., 4H), 6.25(m., 2H), 7.30 (m., 8H), as an oil. The latter compound (12 g.) inanhydrous ether is added dropwise Wit-h efficient stirring to asuspension of lithium aluminium hydride (2.5 g.) in ether (200 ml.). Thereaction mixture is stirred at room temp. overnight, decomposed with 10ml. of water, and the precipitate collected on a filter. The filtrate isdried (MgSO Evaporation of the solutionv gives the title compound, NMR(CDCl 6 1.48 (t., 1H), 2.83 (m., 4H), 3.32 (m., 2H), 6.25 (m., 1H),7.30(m.,4H). I

By following the procedure of this example other starting materials ofFormula II (X =SH), for example those described in Examples 56 to 106are prepared by the appropriate choice of the appropriately substituted3-(2- bromoethyl)-indene derivative prepared from their correspondingstarting material of Formula II (X =O'H) by treatment with phosphorustribromide in carbon tetrachloride.

For example, by replacing 3-(2-bromoethyl)-indene in the procedure ofthis example with an equivalent amount of3-(2-bromoethyl)-5-methoxy-indene, S-methoxyindene- 3-ethanethiol isobtained. Likewise, by replacing 3-(2- bromoethyl)-indene with3-(2-bromo 1 methylpropyl)- indene, a,p-dimethylindene-3-ethanethio isobtained.

l-methyl 1,3,4,9 tetrahydroindeno[2,l-c]-pyran-1- acetic acid (X; R =CHR R R R R and R"'=H, X=O and Y CH COOH) EXAMPLE 2 To a solution ofindene-3-ethanol (8 g.) and methyl acetoacetate (6 g.) in 250 ml. of drybenzene containing hydrated alkali-aluminum silicate (Molecular SievesNo. 4', about 2 g.) is added 1 ml. of boron trifluoride-etherate and themixture stirred at room temperature for 4 hr. An additional 1 ml. ofboron trifluoride-etherate is added, the reaction mixture is stirred atambient temperature overnight and then heated at reflux for 1 hr. Thehydrated alkali-aluminum silicate is collected and the filtrate washedwith 10% solution of sodium bicarbonate and water. After drying overmagnesium sulfate the benzene is removed under reduced pressureaffording l-methyl- 1,3,4,9-tetrahydroindeno[2,1-c1pyran-1-acetic acidmethyl ester,

diluted with water. The aqueous solution is extracted re-' peatedly withether, and acidified with 6 N hydrochloric acid. Theresultingprecipitate is extracted with ether. The ether extract is dried (MgSOfiltered and concentrated. The residue is crystallized from benzene togive the title compound, M.P. 179-180" C., NMR (CDCl 6 1.45 (s., 3H),2.51 (m., 2H), 2.73 (s., 2H), 3.25 (t., 2H), 4.02 (t., 2H), 7.26 (m.,4H), 9.80 (broad, 1H).

An equivalent "amount of ethyl acetoacetate may replace methylacetoacetate in the procedure of this example. In this case,1-methyl-l,3,4,9-tetrahydroindeno[2, 1-c]pyran-1-acetic acid ethyl esteris obtained as the ester. Y

" An equivalent amount of propyl acetoacetate may replace methylacetoacetate in the procedure of this example. In this case,l-methyl-1,3,4,9-tetrahydroindeno[2,

14 1-c]pyran-1-acetic acid propyl ester is obtained as the ester.

EXAMPLE 3 l-methyl 1,3,4,9 tetrahydroindeno[2,l c]pyran 1 propionic acid(X; R =CH R R R R R and R =H, X=O and Y =CH CH COOH) A mixture ofindene-3-ethanol (15 g.), dry benzene (300 ml.), levulinic acid (22.6g.), boron trifluoride etherate (3 ml.) and hydrated alkali-aluminumsilicate (Molecular Sieves No. 4) is stirred at ambient temperature for2 hr.

The reaction mixture is filtered. The filtrate is washed three timeswith 5 N NaOH; the combined aqueous phase is Washed twice with ether andthen rendered acidic with cold diluted HCl. The aqueous phase isextracted with chloroform. The chloroform extract is dried (Na SO andevaporated to dryness. The residue is crystallized from ether-hexane toafford the title compound, M.P. 97-99 0.,

1700, NMR (CDCl 6 1.4 (s., 3H), 2.2 (m., 4H), 2.5 (m., 2H), 3.25 (t.,2H).

EXAMPLE 4- 1-methyl-1,3,4,9 tetrahydroindeno[2,1 c]thiopyran l aceticacid (X; R =CH R R R R R and R"= H, X=S and Y =CH CQOH) A mixture ofindene-3-ethanethiol (8.0 g.), methyl acetoacetate (6 g.) andp-toluenesulfonic acid (0.8 g.) in benzene (200 ml.) is heated at refluxusing a water separator for 5 hr. After cooling, the reaction mixture iswashed with 10% solution of sodium bicarbonate and water. The benzene isremoved under reduced pressure. The residue is the corresponding methylester of the title compound, 1-methy1-1,3,4,9-tetrahydroinden0 [2,1c]thiopyran-l-acetic acid methyl ester,

1730 CHI-1.

The latter ester is dissolved in 200 ml. of methanol and the 100 ml. of1.25 N NaOH is added. After stirring under reflux for 3 hr., themethanol is removed by evaporation and the aqueous residue extractedwith ether. The aqueous-layer is then rendered acidic with 6 N HCl andextracted with ether. The ether extract is dried (MgSO filtered andevaporated to dryness. The residue is crystallized from ether to affordthe title compound, M.P. 119- 121 0.,

sea 3000, 1700 cm."

The procedure of Examples 2 or 4 are followed to prepare other compoundsof Formula X in which R R R R R R R and-X are as defined in the firstinstance and Y is COOR or Alk -COOR wherein R and Alk are as defined inthe first instance. Examples of such compounds of Formula X are listedin Tables I and H. In

' each of these examples an equivalent amount of the starting materialof Formula II listed therein is used instead of the starting material ofFormula II described in the procedures of Examples 2 and 4. Note that ineach of these examples the ester obtained prior to hydrolysis is acorresponding ester compound of Formula X. 1

Similarly, the procedure of Example'3 may be used to prepare theproducts listed in Tables I and II. In this case an equivalent amount ofthe starting material of Formula II, listed therein, is used instead ofthe starting material of Formula II described in Example 3 together withan equivalent amount of the requisite ketoacid.

19 EXAMPLE 107 N,N,1 trimethyl 1,3,4,9 tetrahydroindeno'[2,l"-' c]-pyran 1 acetamide[X; R =CH R R R R R and R =H, X=O and Y =CH CON(CHTriethylamine (12.0 g.) and then ethyl chloroformate (13 g.) in 50 ml.of tetrahydrofuran (THF) are added to a cooled solution (5 C.) of 1methyl 1,3,4,9- tetrahydroindeno[2,1-c]-1-acetic acid (97 g.) describedin Example 2, in 150 ml. of THF. After being stirred for 90 minutes themixture is further cooled to ca. 10 C. and treated with dimethylamine(230 ml. of the 40% aqueous solution) and stirred at 10 C. for anadditional 30 min. Most of the THF is evaporated and the residuepartitioned between chloroform and water. The chloroform layer is washedwith water, dried (MgSO and concentrated to afford the title compound asan oil,

CHOla max.

1625, 1400, 1075 Cm.'" NMR (CDCl 6 1.55 (s., 3H), 3.07 2.53 (m., 2H),2.74 (s., 2H), 2.92 and 3.07 (s., 6H), 3.42 (m., 2H), 3.96 (t., 2H),7.25 (m., 4H).

' In the same manner but replacing the 40% aqueous solution ofdimethylamine with an equivalent amount of the amines of formula HNR Rammonium hydroxide (concentrated), methylamine (40% aqueous solution),n-hexylamine (20% aqueous solution), diethylamine (30% aqueoussolution), isopropylamine (40% aqueous solution), ethylamine (70%aqueous solution), pyrrolidine (50% aqueous solution), piperidine,morpholine, N-methylpiperazine.

1 methyl 1,3,4,9 tetrahydroindeno[2,1 c]pyran 1- acetamide, M.P. 87-880,

CH]: max.

3460, 3340, 1670 cmr N,1 dimethyl 1,3,4,9tetrahydroindeno[2,1-c]pyran-1- acetamide, M.P. 90-91" C.,

CH Cla max.

are obtained, respectively.

By following the procedure of Example 107 but using as starting materialan equivalent amount of one of the acid compounds of Formula X,described in Examples 3 and s to 55, instead ofl-methyl-1,3,4,9-tetrahydroindenoi preparation of the amide. In eachcase the starting ma- [2,1-c]pyran 1 acetic acid, and using anequivalent.

amount of an appropriate amine such as ammonia or a primary or secondaryamine described in Example 107,

then the corresponding amide compound of Formula X is obtained. I

Examples of such amides are listed as products in I Tables III and IVtogether with the appropriate starting material of Formula II with theamine used for the j terialis noted by the example in which it isprepared.

TABLE III No. of the example in which Product: [(prefix listed below)-starting 1,3,4,9-tetrahydroindeno[2,1-c material pyran-l-(sulfix listedbelow)] is pre- Ex pared Amine Prefix/[Suffix 108--. 3 CHsNH:N,1dimethyl//propionamide. 109.-. 3 NH; 1-methyl//propionamide. 110.-. 3(CHahNH N,N,l-trimethyl//propionamide,

NMR(ODC1 6 1.40 (3H), 2.14 (4H), 2.47 (2H), 2.85 and 2.89 (6H), 3.30(2H), 3.95, (2H) 7.25 (4H). 111--- s CzHsNHz N-ethyl-1-methy1//proionamide. 112--. 3 (CzHmNH N,Nadiethyl-1-methyl /propionam e. 113.-.(CHahNH N,N,1-trimethy1//carboxamide,NMR

CD013) 5 1.68 (s, 3H), 2.65 (m, 2H), 3.12 (s, 6H), 3.54 (m, 2H), 4.08(m, 2H), 7.23 (m, 411). 114... 5 NH; 1-methy1//carboxamide. 115.-. 6(CHmNH l-ethgl-N,N,3-trimethyl//carboxam e. 116--- 7 11-CflH13NH21,3-diis0 ropyl-6,9-dimethyl-N- hexyl /carboxamide. 117-.- 8 CzHsNHzN-ethyl-fi-hydroxy-l,3,3-trimethyl// carboxarnide. 118... 9 CHaNHz8,9-diethyl-N-methy1-1-propyl// earboxamide. 10 (CHQZNHl-butyl-N,N-dimethyl-4,9-diisopropyl//carboxamide. 11 HmNH1-buty1-4,4,Q-triethyl-N,N,3.3-tetramethy1//carboxamide. 12 CHaNHQN,1,4-trimethyl//acetamide. 13 N H3 1-ethy1//acetamide. 13 (OHs)zNHN,N-dimethyl-1-ethy1//acetamide. 13 n-CflH NHzl-ethyl-N-hexyU/acetamide. 13 (C2H5)2NH N,N,1-triethyl//acetamide. 14CHQNHZ N-methyl-1-propy1//aeetamide. 14 NH 1-pr0py1//acetamide. 14(CHQZNH N,N-dimethyl-1-propy1//acetamide. 14 Il-CBHHNHIN-hexyl-l-propyU/aeetamide. 14 (C2H5)2NHN,N-diethy1-1-propy1//aeetamide. 15 aNHz 1-isopropyl-N-methyU/acetamide.15 zHmNH N,N-diethyl-1-isopropy1//aeetamide. 16 HaNHz N,3-dimethy1-1-propy1//acetamide. 16 (CH2)2NHl-progyl-N,N,3-trimethyl//acetam1 e. 17 (CzHmNH3,9-dimethyl-N,N,1,4-tetraethyl// acetamide. 18 CHaNHN,u,1,Q-tetramethyU/acetamide. 18 NHa a,1,9-trimethy1//acetamide. 18(CH3)2NH N N,a 1,9-pentamethyl//aeetamide. 19 0211510121-butyl-N,9-diethyl-a,a-dimethylfl acetamide. 20 CHaNHgl-t-butyl-N-methyl//acetamlde. 21 CHgNHz 1-buty1-N-mcthyl//aeetamide. 22C2H5NH2 N,9-diethyl-S-methyl-l-propyl/l aeetamide. 3 2H5)zNH6-brono-N,N,1,9-tetraethyl//acetam1 e. 24 NH; 1,6-dimethyl//aceta.m.lde.25 t-C4H9NHI 6-acetoxy-N,9-di-t-buty1-l-methyl// acetamide. 26 NH;G-benzyloxy-Q-isopropyl-l-methyll/ acetami e. 27 (CHmNHl-propyl-N,N,5,9-tetramethylll aeetamide. 28 (C2Ha)2NHN,N-diethy1-7-methyl-1-propyl/l acetamide. 29 n-CoHmNHz1,9didpropyl-N-hexyl-6-nitro/lacetanu e. 150.... 30 CHaNHzl-propyl-N,4,4,9-tetramethyl/l acetamide. 151..- 31 NH;3,3-dimethy1-6-ethoxy-a,a,1-tr1- ethyl/lacetamide. 152--. 32 CZHENH:1,9-dibutyl-a,a,3,3-tetramethyl- N ,4,4,7-tetraethyl/lacetamide. 153...33 CH3NHz. 1-ethy1-N,a,3,9-tetramethy1-4,4.9-

tripropyll/aeetamide. 154--- 34 (CHQZNHI 1-propy1-N,N,a,a-tetramethyl/laeetamide. 155..- 35 (C2H5)zNHg 1t-butyl-a,a-diisopropyl-N,N,3,3-

' 4,4,5,Q-QctaethyI/Iacetamidta. 156..- 36 CHaNHz N,Q-dimethyl-fi-iodo-l-isopropyl/l propionamide. 157-.. 38 CHflNHB fl,3-diethy1-N,9-dlmethyl-7-hydroxyl-propyll/propionamide. 158--- 39 NH;1-buty1-3,Q-dimethyl-B-nitro-flpropyl/lpropionamide. 159... 43 CzHsNHa5,8,4,4-tetramethyl-N,l,9-triethy1// propionamide. 160... 45 n-CaH1NHza,9-d.imethyl-5-methoxy-N,1.3- tripropropyl/Ipropionamide.

161... 48 C2H NHz 1-butyl-7-ethoxy-N,a,fl,9-tetraethylll propionamide.162..- 49 CHaNH: N,l-dimethyl//butyramide. 163.-. 49 (CHmNH N,N.1-trimethy1/Ibutyramide. 164.... 52 Ii-C4H9NH2N,1-dibutyl-3-ethyl-7-nitro-afi trimethyl/lbutyramide. 165..- 53(n-CaH1)2NH a,B-diethyl-3,3-dimethyl-N,N,1,5,9-

pentapropyl/lbutyramide. 1 5 I1' 4 DNHz N,9-dibutyl-l-ethyl-lZ-hydroxya,a, ,'y-tetramethylflbutyrernide. 167-..(-tC4Hu)2NH 5-eth0Xy-1-ethyl-u,a,fi,fi,'y,'y,3,4

By following t e pro edure of lixarnpb 28 r butusing as startingmaterial an equivalent amount of one of the amide compounds of Formula Xdescribed in Examples 108 to 195 instead of N,N,1-trimethyl-l,3,4,9-tetrahydroindeno[2, 1-c]pyranl-acetamide, then thecorresponding compounds of Formula 1 are obt'ainedjExam'ples of suchcompounds of Formula 1 are listed as products in Table VII and VIIItogether with the appropriate starting material. In each case thestarting material is noted by the example in which it is prepared.

TABLE VII N o. of example in which Product: [(pr'efix listedbelow)-1,3,4 Q-tetrahystarting indeno[2,l-c]-pyran-1-(suflix listedbelow)] material Example is prepared Prefix/[Suffix 108N,1-dimethyI//propylamine. l-methyll/propylamine.

N,N,1-trlmethy1//propylamine, nmr (CD013) 6 1. (s, 13H) 3.30 (m, 2H),3.94 2H); correlsfondmg ydrochloric acid addition salt has .P. 210212 C,after recrystallization from isopropanol.

N-ethyl-l-methylI/pro ylamine.

N,N-diethyl-l-methylfipropylamine.

N,N,1-trlmethyl/lmethylamine, nmr (CD013) 6 1.45 (s, 3H), 3.35 (m, 4H),3.94 (m, 211); corresponding hydrochloric acid addition salt has M.P.250-251" C after recrystallization from iso ropanol.

.l-methyl/ methylamine.

Lethyl-N ,N,3-trimethylllmethylamine.

1,8-di sopropyl-G,Q-dimethyl-N-hexyl//methylamine.N-ethyl-G-hydroxy-l,3,3-trlmethylllmethylamine.8,9-diethyl-N-methyl-1-propyl//methylamine.l-butyl-N,N-dimethyl-4,9-diisopropyl//methylamine.1,9dibutyl-N,4,4,7-tetraethyl-,a,3,3- tetramethyll/ethylamine.

l-ethyl-N,a,3,9-tetramethyl-4,4,9-tripropylll. ethylamine.l-propyl-N,N,a,a-tetramethylllethylamine.Lt'butyI-a,a-diisopropyl-N,N,3,3,4,4,5,9-

octaethyll/ethylamine. N,9-dimethyl-54odo-l-isopropyl//propylamine.B,B-dieth 1-N,9-d.imethyl-7-hydroxy-1- propyl lpropylamin'e.1-butyl-3,Q-dimethyl-8-nitro-B-propyl// propylamine. fl,B,4,t-tetramethyl-N,1,9-t1iethyl/lpropylamine.a,Q-dimethyl-fi-methoxy-N,l,3-tripropyl/l prop amine. 1-buty1-7-ethoxy-N,a,fi,9-tetraethylllpropyl- TABLE VIII No. of i 1 examplein Product: .(prefix listed be1ow)-1,3,4,9-tetrahywhichdrolndeno'[2,1-c]-pyran-1-YL)-(suflix listed 1 starting below)] materialis prepared EXAMPLE 373 N,N,1-trimethyl 1,3,4,9tetrahydroindeno[2,1-c]thiopyran-l-ethylamine [1; R =CH R R R R R and R=H and Y=CH CH N(CH The amide, N,N,1-trimethyl-1,3,4,9 tetrahydroindeno-[2,1-c]thiopyran-l-acetamide' (2.7 g.), described in EX- ample 196, inanhydrous ether (200 ml.) is added dropwise to a stirred suspension oflithium aluminum hydride (1.0 g.) in ml. of anhydrous ether. The mixtureis stirred at room temperature for 30 min. Excess hydride is decomposedwith water (4 ml.). The mixture is filtered. The filtrate is dried (MgSOand concentrated to give the title compound, NMR (CDCl;.,), 1.45 (s.,3H), 3.50 (m., 2H), 7.32 (m., 4H).

The corresponding hydrochloric acid addition salt, N,N,1-trimethyl1,3,4,9 tetrahydroindeno[2,l-c] thiopyran-l-ethylamine hydrochloride,has M.P. 265-267 C. after recrystallization from ethanol.

In the same manner but replacing lithium aluminum hydride with anequivalent amount of lithium aluminum hydride-aluminum chloride,aluminum hydride-aluminum chloride, diborane and sodiumborohydride-aluminum chloride, the title compound is also obtained.

In the same manner but replacing N,N,1-trimethyl-1,3,4,9-tetrahydroindeno[2,1-c1thiopyran 1 acetamide with an equivalentamount of the appropriate amide described in Example 196', then thefollowing corresponding indenothiopyranalkylamines are obtained:

l-methyl- 1,3 ,4, 9-tetrahydroindeno [2, l -c] thiopyranl-ethylamine, N,l-dimethyl-1,3,4,9-tetrahydroindeno [2, l-c] thiopyranl-ethylamine,N-hexyl-1methyl-1,3,4,9-tetrahydroindeno [2,1-c]

thiopyran-l-ethylamine, N,N-diethy1- l-methyl- 1 ,3,4,9-tetrahydroindeno [2, l-c] thiopyran-l-ethylamine,1-methy1-N-isopropyl-1,3 ,4,9-tetrahydroindeno [2,1-c]

thiopyran-l-ethylamine, I N-ethyl-l-methyl-l,3,4,9-tetrahydroindeno[2,1-c]

' thiopyran-l-ethylamine, 1- 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]thio1 pyran-l-yl) ethyl1-pyrro1idine,

27 1- l-methyl-l,3,4,9-tetrahydroindeno [2,1-c1thiopyranl-yl) ethyl]piperidine, 4- 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c]thiopyran-1-)ethyl] -morpholine, and 1-methyl-4-l-methyl-1,3,4,9-tetrahydroindeno[2,1-c]

thiopyran-1-yl)-ethyl]piperazine, respectively.

By following the procedure of Example 373 but using as starting materialan equivalent amount of one of the amide compounds of Formula X (X=S),described in Examples 197 to 284 instead of N,N,1-trimethyl-1,3,4,9-tetrahydroindeno[2,1-c]thiopyran-l-acetamide, then the correspondingcompounds of Formula I are obtained. Examples of such compounds ofFormula I are listed as products in Table IX and X together with theappropriate starting material. In each case the starting material isnoted by the example in which it is prepared.

TABLE IX No. of example in which starting Product: [(prefix listedbelow)-1,3 4,9-tetramaterial hydroindeno[2,1-c]-thiopyran-1-(suflixlisted is prebelow)] N l-dimethyll/propylamine. l-methyll/propylamine.

N N l-trimethyll/propylamine.

N N-diethyl-l-methyll/propylamine.

N N l-trimethyl/lmethylamine. l-methyl/lmethylamine.

l-ethyl-N N 3-trimethyl/lmethylamine.

1, 3-diisopropyl-6, 9-dimethyl-N-hexyll/methylamine. N-ethylfi-hydroxy-l3, 3-t1imetl1yll/methylmm 8, 9-diethyl-N-methyl-l-propylllmethylamine.l-butyl-N, N-dimethy1-49-diisopropyl/lmethylamine. l-butyl-t, 4,Q-triethyl-N, N,3, 3-tetramethy1l/ amine.l-t-butyl-N-methyl/lethylamine. 1-butyl-N-methyl//ethylamine.

N, 9-diethy1-8 methy1-1-propyl// ethylamine. 6-bromo-N,N,1,Q-tetraethyl/lethylamine. 9-butyl-6-methoxy-l-methyl//ethylamine.fi-acetoxy-N, Q-di-t-butyl-l-methyl/lethylamine.G-benzyloxy-Q-isopropyl-l-methyl//ethyla ne.1-propyl-N,N,5,Q-tetramethyll/ethylamine.N,N-diethyl-7-methyl-l-propyll/ethylamine.1,9-dipropyl-N-hexyl-6-nitro/lethylamine.l-propyl-N,4,4,9-tetramethyl//ethylamiue.3,3-dimethyl-6-ethoxy-a,a,l-triethyl/lethylamine. 1,9-dibutyl-N,44,7-tetraethyl-a,a,3,3-tetramethyl/lethy amine.l-ethyl-N,a,3,9-tetramethyl-4,4,9-tripropyl/l ethylamine. 1-propyl-N,Na,a-tetramethyl/lethylarnine. l-t-butyl-a a-diisopropyl-N,N,3,3,4,4,5,9-

octaethy I/ethylamine. N-methyl-l-propyl/lpro ylamine. N,N-dimethyl-1-propyl lpropylamine.1-butyl-3,9-dimethyl-8-nitro-fl-propyll/propylamine. fl, 3,4,i-tetramethyl-N,1,Q-trlethyll/propylflmlll ea,9-dimethyl--methoxy-N,1,3-tripropyl/l propylamine.1-butyl-7-cthoxy-N,01,19,Q-tetraethyll/propylamN,1-dimethyl//butylamine. N,N,l-trimethylllbutylamine.N,1-dibutyl-3-ethy1-7-nitro-a,B,'y-trimethy1// butylamine.a,8,-diethyl-3,3-dimethyl-N,N,1,5,9-pentapropyl/lbutylamine.N,Q-dibutyl-I-ethyl-8-hydroxy-a,a,'y,'y-tetramethyl/lbutylamine.5'ethoxy-1-ethyl-a,a, 9,B,'y ,3 4-oetamethy1- N ,,N9-tri-t-butyl//butyne.

Example TABLE X Product: [(prefix listed below)-l,3,4,9-tetrahydroindeno52,1-c]thiopyran-1-yl)-(suflix listed below) preparedl-[(l-methyl//propyl pyrrolldine.

1-[(l-methyl//propyl piperidine.

4-[(l-methyl/lpropyl morpholine.

1-[(l-methyl//propyl piperazine.

l-methyl-4[(1-methyl//propyl]piperazine.

pip azure. l-[(1-methyl//methyl pyrrolldine. 't-[O-methylflmethylmorpholine. 1-ethy1-4-[(1eth I-B-methyl/lmethyl]piperazlne1-[(1,4-dimethyl IethyHpiperidine. 4-[(1-ethyll/ethyllmorpholine.1-(3-11ydroxypropyl)-4-[(1-ethy1//ethyl]pipera ne.l-[(l-propyl/lethyl}pyrrolidine. 4-[(l-propyll/ethyl morpholine.1-[(l-isopropyl/lethyl]piperzine.1-[(B-methyl-l-propyll/ethyl]piperazine.1-ethyl-4-[(a,1,Q-tIimethyII/ethyl]piperazine.1-[(fi-benzyloxyl-9-isopropyl-l-methyll/ethyl]- pyrrolidine.1-[(5,9dimethyl-1-pro yl/lethylIprperzme. 4[(3,3-dimethyl-6 metoxy-u,a,1-trrethyl// heptamethyll/propyl]piperazme.1-[(1,3,Q-trimethyl-a,a-dipropyll/propyl] yrrohdine. 4421,9-diethyl-B,fl,4,4-tetramethyl/lpropyl] morpholine.1-propyl-4-[(1-butyl-7-ethoxy-a,fl,9-triethyl// ropyl]piperazine.l-Rl-methyl/lbutyl]pyrrolidinc.l-(hydroxymethyl)-4-[(1-methyl//butyl]piperazme.1-[1-ethyl-'y,39-trimethylllbutyl]pipendine.

EXAMPLE 461 N,N,1-trimethyl 1,3,4,9tetrahydroindeno[2,1-c1pyranl-carboxamide [Xg R =CH R R R R R and R =H,X=O and Y -=CON(CH A mixture of indene-3-ethanol (500 mg.)N,N-dimethyl-pyruvamide (580 mg.), described by W. F. Gresham in US.Patent 2,429,877, issued Oct. 28, 1947, 1.7 g. of phosphorus pentoxide,0.5 g. of diatomaceous earth (Celite) in ml. of benzene is stirred atroom temperature for 15 min. and then at 70 C. for 1 /2 hr. The reactionmixture is filtered. The filtrate is washed with water, dried (MgSO andconcentrated to give the titled compound, identical to the product ofExample 113.

In the same manner but using an equivalent amount of the appropriatestarting material of Formula II in place of indene-S-ethanol togetherwith the appropriate a-, 5-, 'yor 5-ketoamide, the products listed inTables III, IV, V and VI and Examples 107 and 284 are obtained. Forexample, by using 5-methylindene-3-ethanol, described by I. A. Elvidgeand R. G. Foster, J. Chem. Soc., 590 (1963), and the fl-ketoamide,acetoacetamide in the procedure of this example,1,6-dimethyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-l-acetamide,identical to the product of Example 144, is obtained.

EXAMPLE 462 l-methyl-l,3,4,9-tetrahydroindeno[2,1-c]pyran 1 methand (X;R =CH R R R R R and R"=I-I, 76:0, and Y =CH OH) Procedure A The acidintermediate of Formula X, 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-carboxylic acid (10.4 g.), described inExample 5, in ml. of THF is slowly added to a stirred mixture of lithiumaluminum hydride (2 g.) in 100 ml. of THF. The reaction is kept at 0 C.using an ice-water bath. After addition of the acid, the excess of thehydride is destroyed with water and the precipitate is collected on afilter pad. The filtrate is evaporated. The residue is taken into etherand the ether phase is washed with water, dried (Na SO and evaporated atwere to an;o il. Chromatography of the oil -on-silica gel usingchloroform gives the title comifp ll i .1, 3 I I Q 1 3580, 3440, 1470,1120, 1095, 1075, 1050 cmr' NMR (CDC1 1.32 (s., 3H), 2.02 (broad, 1H),2.49 m., 2H), 3.26 (t., =2H), 3.62. (s., 2H),:3. 95 (t., 2H), 7.21 (m.,4H).

' 1 Y Procedure B r I Alternatively, the title compound is also obtainedby following the procedure of Example 2 but replacing methylacetoacetate with an' ,equiva1ent amount of the ketoalcohol lower alkylester acetoxyacetone. Note that the procedure of said example includeshydrolysis of the intermediateester. I EXAMPLE 463 N,N -ltrirnethyl1,3,4,9 tetrahydroindeno[2,1-c]pyran- 1 methyl 1,3,4,9tetrahydroindeno[2,1-c]pyran-1- methanol (90 g.); described in Example462, is dissolved in .dry pridine (20 ml.). p-Toluenesulfonyl chloride(7.4 g.) is added porti'onwise tothe vigrously stirred and cooledsolution. The mixture is stirred further at C. for 1 hr., ice and wateris then added. and the aqueous mixture is extracted with ether. Thecombined ether extracts are washed with 10% ice-cold, hydrochloric acid,water, 5% sodium bicarbonatewate'r and dried (Na SO Concentration of theextracts aifords'1-methyl-1,3,4,9-tetrahy- 'droindeno[2,1-c]pyran-1'-methyl tosylate.

' The'latter tosylate (11.7 g.) is' dissolved in dry acetone (100 ml.)and the resulting solution treated with sodium iodide (15 g.).[Themixture is stirred at room temperatiure for 24 hr. Most of the acetoneis removed at reduced pressure, water and ice are added and theresulting browncolored' solution is extracted with ether. The combinede'ther extracts are washed with sodium thiosulfate solution, water anddried (Na SO The solvent is evapat room temperature for6 hr. Most of thetetrahydrofuran 'is' removed at reduced pressure, the milk watersolution is extracted with ether and washed with water until the watertests neutral. The extract is dried (Na S0 and evaporatedto yield thevtitle compound, identical to the product of Example 290.

By following theprocedureof Examples 462 and 463 in sequence but usingas starting material in Example 462 .an equivalent amount of theappropriate ester intermediate of Formula .X,(in the case of ProcedureA) or an appropriatenstarting material of Formula II and appropriateketo alcoliol-,l c wer alkyl,ester of Formula, IX, described above, (inthecase ,of Procedure B); followed by the use .of an appropriate amine.of Formula HN IP, for examv. pleth e amines described .in Example 107,in the proce- ,dureofExample 463, then the respective compounds of.Formula I, for example those described in Examples 284 to 460, areobtained.

EXAMPLE 4 64 Q. Y

N,1-dimethyl 1,3,4,9 -,tetrahydroindeno[2,1-c]pyran-lpropylaminell; R CH3 4 a e and R =H, X=O and Y=CH CH CH NH(CH A solution'oftriethyloxonium'fluoroborate (3.5 g.)

and'the amideiof-Formula X, N,l-dimethyl-l,3,4,9-tetra- -hydroindenoE2,1-0]pyran-l-propionamide (5.5 g.), de-

scribed id-Example 108, in 100 ml. of methylene chloride is evaporatedat reduced pressure and the residue dissolved in 50 ml. of absoluteethanol. Sodium borohydride (1.35. g.) is added in portions to thestirred solution at 0 C. When the addition is complete, stirring iscontinued for 18- hr. at 25 C. The solution is poured into 250 ml. ofwater and extracted with 3 X30 ml. portionsof ether. The combinedextracts are washed with water, dried (MgSO and evaporated yielding thetitle compound, identical to the product of Example 285.

Similarly other amides of Formula X, for example those described inExamples 107 to 283, may be reduced to their corresponding indenopyranorindenothiopyranalkylamines of Formula I.

EXAMPLE 465 l-methyl- 1,3 ,4,9-tetrahydroindeno [2,1-c]pyran-1-carboxaldehyde N,N-dicyclohexylcarbodiimide (2.87 g.) is added to acooled, stirred solution of the primary alcohol, l-methyl- 1,3,4,9tetrahydroindeno[2,1-c]pyran-1-methanol (1.09 g.), described in Example462, in 10 ml. of dimethyl sulfoxide-benzene (2:1) containingtrifluoroacetic acid (0.18 ml.) and pyridine (0.38 tnl.). The reactionis stirred at room temperature under nitrogen for 5 hr. The reactionmixture is now diluted with ml. of ether, followed by the dropwiseaddition of a solution of oxalic acid (1.26 g.) in 6 ml. of methanol.After thirty minutes, water (100 ml.) is added and the insolublematerial is collected. The organic phase is washed with water (2X 5%aqueous sodium bicarbonate (2X) and water (2x Afer drying (MgSO theorganic phase is evaporated to yield an oil. The oil is purified bychromatography on silica gel. Elution with 10% ether in benzene affordsthe title compound as an oil EXAMPLE 466 The product of Example 465 istreated with dimethylamine and perchloric acid according to the methodof N. J. 'Leonard and J. V. Paukstelis, J. Org. Chem, 28, 3021 (1963),to yield to corresponding immonium salt. Reduction of the lattercompound with sodium borohydride according to the procedure described byE. Schenker, Angew. Chem., 73, 81 (1961), affords the title compound,identical to the product of Example 290.

By following the procedure of Examples 462, 465 and 466 in sequence butusing as starting material in Example 462 an equivalent amount of theappropriate acid intermediate of Formula X (in the case of Procedure A)or an appropriate starting material of Formula II and the appropriateketo-alcohol lower alkyl ester of Formula IX, described above, (in thecase of Procedure B), followed by the use of an appropriate amine offormula HNR R for example the amines described in Example 107, in theprocedure of Example 465, then the respective compounds of Formula I,for example those described in Examples 284 to 460, are obtained.

' .VEXAMPLE 467 Oxidation of l-methyl-1,3,4,9-tetrahydroindeno[2,l-c]=pyran-1-carboxaldehyde, described in Example 465, with 1 '-By'following the procedure of Examples 462, 465 and 467, insequence, butusing as starting material in Example 462 an equivalent amount oftheappropriate acid intermediate of Formula IX (in the case of 'ProcedureA) or an appropriate starting material of Formula II and 3-1 appropriateketoalcohol lower alkyl ester of Formula IX, described above (in thecase of Procedure B); then the respective acid compounds of Formula X inwhich Y is COOH or AIk COOH wherein Alk is as defined in the firstinstance, for example the products of Examples 6 to 106, are obtained.

EXAMPLE 468 l-methyl 1,3,4,9 tetrahydroindeno[2,l-c]pyran-1-methylamine[1; R =CH R R R R R and R =H, X=O and Y=CH NH A solution of thealdehyde, l-methyl-l,3,4,9-tetrahydroindeno[2,1 c]pyran 1-carboxaldehyde (1.0 g.), de scribed in Example 465, aqueoushydroxylamine hydrochloride (5 ml. of 5 N) and aqueous sodium acetate(5.0 ml. of 5 N) and methanol (10 ml.) is heated at 50- 60 C. for 5 min.and then kept at 4 C. for 16 hr. The precipitate is collected andrecrystallized from ethanolwater to afford the corresponding oxime ofthe above aldehyde.

The latter compound (230 mg.) in dry THF (10 ml.) is added dropwise to astirred mixture of lithium aluminum hydride (200 mg.) in ml. of THF atice bath temperature. The mixture is stirred for 1 hr., during whichtime it is allowed to come to room temperature. Excess lithium aluminumhydride is destroyed by the careful addition of H O/THF (1: 1).Insoluble material is collected on a filter and filtrate isconcentrated. The concentrate is taken up in ether. The ether solutionis dried (MgSO filtered and concentrated to afford the title compound,identical with the product of Example 291.

By following the procedures of Examples 462, 465 and 468, in sequence,but using as starting material in Example 462 an equivalent amount ofthe appropriate acid intermediate of Formula X (in case of Procedure A)or an appropriate starting material of Formula 11 together with anappropriate ketoalcohol lower alkyl ester of Formula IX, describedabove, then the respective primary amine of Formula I is obtained. Morespecifically exemplified, by replacing l-methyl l,3,4,9 tetrahydroindeno[2,l-c]pyran-1-carboxylic acid with an equivalent amount of 3,3-dimethyl6 ethoxy-u,atriethyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-acetic acid,described in Example 31, in the procedure of Example 462 and subjectingthe product thereof to the procedures of Example 465 and 46 8, then 3,3dimethyl 6 ethoxy-a,a,1-triethyl-l,3,4,9-tetrahydroindeno[2,1-c]pyran-1-ethylamine, identical to the product ofExample 328, is obtained.

EXAMPLE 469 1-3-iodomethyl) l methyl 1,3,4,9 tetrahydroindeno-[2,1-c]pyran-(X; R =CH R R R R R and R' =H, X=O and Y =CH l) To asolution of indene-3-ethanol (15 g.) in 150 ml. of benzene, iodoacetone(12 g.) is added. The mixture is heated at reflux with 5 ml. of borontrifluoride-etherate and hydrated alkali-aluminum silicate (MolecularSieves No. 4). After one hour 400 mg. more of acid is added. After atotal of two hours the reaction is cooled, filtered and washed with 5%sodium bicarbonate, water and dried over sodium sulfate. Evaporationunder reduced pressure affords an oil. This oil is purified bychromatography on silica gel. Elution with benzene and concentration ofthe eluate gives the title compound, identical to the compound of thesame name described in Example 463.

By following the procedure of Example 469 but using as startingmaterials an appropriate startingmaterial of Formula II, describedabove, together with an appropriate 3, or B-haloketone of Formula IVdescribed. above, then the corresponding intermediates of Formula X (Y=Alk -L in which Alk and L are as described in the first instance) areobtained.

In turn the last said intermediates of Formula X is treated according toconditions described in Example 463 with an appropriate amine of formulaHNR R in which R and R are as described in the first instance to 'yieldthe corresponding compounds of Formula I, for instance the products ofExamples 284 to 289, and 386 to 438.

EXAMPLE 470 N-ethyl l methyl 1,3,4,5 tetrahydroindeno[2,l-c] pyran lpropylamine [I; R .=CH R R R R R and R"=H, X=O and Y'==CH CH NH(C H Amixture of indene-3-ethanol (4.2 g.) and N-(4- oxopentyl)acetamide (3.7-g.), described by L. P. Kuhn et al., J. Am. Chem. Soc., 89, 3858(1967), in 300 ml. of dry benzene is stirred and heated at reflux. Wateris collected in a Dean-Stark trap. After removal, of the water fivedrops of boron trifluoride-etherate is added and the mixture refluxed 30min. using the water-separator again. After stirring at room temperatureovernight the reaction mixture is evaporated to dryness. The solidresidue is dissolved in chloroform and washed successively with 10%aqueous sodium bicarbonate, water, and brine. The chloroform solution isdried over magnesium sulfate, and filtered, and evaporated to yield 1-[3-(acetamido)propyl]- 1-methyl-l,3,4,9-tetrahydroindeno[2,1-c]pyran,

i859? 1650 cmf The latter product (2.6 g.) in ml. of dry THF is added toa suspension of lithium aluminum hydride in 200 ml. of THF. Theresultant slurry is stirred and heated as reflux for 2 hours, cooled and2.4 g. of lithium aluminum hydride is added. The mixture is heated atreflux for 16 hrs. The mixture is then decomposed with 22.4 ml. of wateradded dropwise over 3 hrs. while stirring and cooling the mixture. Theprecipitate is separated by tiltration. The filtrate is dried (MgSORemoval of the solvent affords the title compound, identical to theproduct of Example 288.

By following the procedure of Example 470, but using as startingmaterial an equivalent amount of the appropriate starting material ofFormula II, for example, those described in Examples 2 to 106 and usingan equivalent amount of an appropriate ketoamide of formula describedabove, then the respective secondary amine compounds of Formula I areobtained.

EXAMPLE 471 1-methyl 1 (3-nitropropyl) 1,3,4,9 tetrahydroindeno-[2,1-c]pyran (X; R; =CH R R R R R and R"=H, X=O and Z=CH CH NO To asolution of 352 mg. of indene-3-ethanol and 273 mg. of the nitroketone,5-nitro-2-pentanone, H. Shechter, et al., cited above, in ml. of benzeneis added 5 drops of boron trifluoride etherate and three drops oftrifluoroacetic acid. The reaction mixture is stirred and heated atreflux under a water-separator for 18 hours. The benzene solution iscooled, washed with 10% sodium bicarbonate solution, water, saturatedbrine solution, and dried over magnesium sulfate. The solvent is removedand the residue is subjected to chromatography on silica gel.Elution'with chloroform gives the title compound,

CHOI! max.

1550 cmr a i Reduction of the latter compound with lithium aluminumhydride according to theprocedure of Example 464 affords l-methyl1,3,4,9 tetrahydroindeno[2,l-c] pyran-I-propylamine, identical to theproduct of Example 286.

/ By following the procedure of Example 471 including the reductiondescribed therein but using as starting material an equivalent amount ofthe appropriate starting material of Formula II, for example, thosedescribed in Examples 2 to 106, and using an equivalent amount of anappropriate nitroketone of formula described above, then the respectiveprimary amine compounds of Formula I are obtained.

EXAMPLE 472 N,N, 1 trimethyl-1,3,4,9-tetrahydroindeno [2, l-c]-pyranl-ethylarnine (1; R =CH R R R R R and R"=H, X=O and Z=CH CH N(CHTo a solution of 1-dimethylamino-3-butanone (1.0 g.) dissolved intoluene ml.), p-toluenesulfonic acid (1.3 g.) is added. The suspensionis stirred for 10 min. Indene- 3-ethanol (1.0 g.) in toluene (5 ml.) isadded to the suspension and the resulting solution stirred for 2 hr.Boron trifluoride etherate (0.25 ml.) is added together with ca. 0.5 g.of hydrated alkali-aluminum silicate. The mixture is heated at 80 C. for30 min. The mixture is cooled and diluted with water. The organic layeris separated and the aqueous layer extracted with toluene. The organiclayers are washed with water. The combined aqueous phase is renderedalkaline with cone. NH OH and extracted with toluene. The latter extractis treated with charcoal and then concentrated to alford the titlecompound, identical to the compound of the same name described inExample 284.

By following the procedure of Example 471, but using as startingmaterial an equivalent amount of the appropriate starting material ofFormula 11, for example, those described in Examples 2 and 106 and usingan equivalent amount of the appropriate aminoketone of formula RCO-AIk-NRtR wherein R Alk, R and R are as defined in the first instance,then the respective indenopyranand indenochropyranalkylamines of Formula1 are obtained.

We claim: 1. A compound selected from those of formula in which R islower alkyl; R R R and R are the same or different selected from thegroup consisting of hydrogen and lower alkyl; R is hydrogen, loweralkyl, hydroxy, lower alkoxy, lower alkanoyloxy or halo; R is hydrogenor lower alkyl; X is oxy or thio; and Y is an amino(lower)alkyl radicalof formula -Alk-NR R wherein Alk is an alkylene selected from the groupconsisting f CRIORII CRIORIICRIZRH, CRIURIICRIZRHCRMRIE and CR R CR R CRR CR R wherein R R R R R R R and R are hydrogen or lower alkyl and R andR are either the same or diiferent selected from the group consisting ofhydrogen and lower alkyl, or R and R together with the nitrogen atom towhich they are joined form a heterocyclic amine radical selected fromthe group consisting of l-pyrrolidinyl, piperidino, morpholino,piperazino, 4-(lower alkyl)-1- piperazinyl and4-[hydroxy(lower)alkyl]-1piperazinyl, and the acid addition saltsthereof with pharmaceutically acceptable acids. v

2. N,N,1-trimethyl 1,3,4,9 tetrahydroindeno[2,1-c]- pyran-l-ethylamine,as claimed in claim 1.

3. N,N,l-trimethyl 1,3,4,9 tetrahydroindeno[2,1-c]- pyran-l-ethylaminehydrochloride, as claimed in claim 1.

4. N,N,1-trimethyl 1,3,4,9 tetrahydroindeno[2,1-c]- pyran-l-propylamine,as claimed in claim 1.

5. N,N,1-trimethyl 1,3,4,9 tetrahydroin1eno[2,l-c]- pyran-l-propylaminehydrochloride, as claimed in claim 1.

6. N,N,1-trimethyl 1,3,4,9 tetrahydroindeno[2,1-c]- pyran-l-methylamine,as claimed in claim 1.

7. N,N,1-trimethyl 1,3,4,9 tetrahydroindeno[2,l-c]- pyran-l-methylaminehydrochloride, as claimed in claim 1.

8. N,N,1-trimethyl 1,3,4,9 tetrahydroindeno[2,1-c]-thiopyran-l-ethylamine, as claimed in claim 1.

9. N,N,1-trirnethyl 1,3,4,9 tetrahydroindeno[2,l-c]-thiopyran-l-ethylamine hydrochloride, as claimed in claim 1.

References Cited UNITED STATES PATENTS 4/ 1969 Faust et a1. 260-309.66/1970 Von Strandtmann et al.

US. Cl. X.R.

424-248, 250, 267, 274, 275, 283; 260-2471, 247.2 B, 247.7, 268 TR,293.57, 293.58, 326.3, 326.5 CA, 326.5 SA, 326.84, 345.2, 488 CD, 609 D,611 F, 618 F

